title: Overexpression of mitochondrial cholesterol delivery protein, StAR, decreases intracellular lipids and inflammatory factors secretion in macrophages.
abstract: Hyperlipidemia is one of the most important risk factors for atherosclerosis. This can be amplified by a localized inflammatory response mediated by macrophages. Macrophages are capable of taking up excess cholesterol, and it is well known that delivery of cholesterol to the mitochondria by steroidogenic acute regulatory (StAR) protein is the rate-limiting step for cholesterol degradation in the liver. It has also been shown that overexpression of StAR in hepatocytes dramatically increases the amount of regulatory oxysterols in the nucleus, which play an important role in the maintenance of intracellular lipid homeostasis. The goal of the present study was to determine whether StAR plays a similar role in macrophages. We have found that overexpression of StAR in human THP-1 monocyte-derived macrophages decreases intracellular lipid levels, activates liver X receptor alpha (LXRalpha) and proliferation peroxysome activator receptor gamma (PPARgamma), and increases ABCG1 and CYP27A1 expression. Furthermore, it reduces the secretion of inflammatory factors, and prevents apoptosis. These results suggest that StAR delivers cholesterol to mitochondria where regulatory oxysterols are generated. Regulatory oxysterols can in turn activate nuclear receptors, which increase expression of cholesterol efflux transporters, and decrease secretion of inflammatory factors. These effects can prevent macrophage apoptosis. These results imply a potential role of StAR in the prevention of atherosclerosis.
authors.affiliation: Department of Physiology & Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, PR China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Ning
authors.forename: Qianming
authors.initials: Q
authors.lastname: Bai
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Li
authors.forename: William M
authors.initials: WM
authors.lastname: Pandak
authors.forename: Fengdi
authors.initials: F
authors.lastname: Zhao
authors.forename: Sifeng
authors.initials: S
authors.lastname: Chen
authors.forename: Shunlin
authors.initials: S
authors.lastname: Ren
authors.forename: Lianhua
authors.initials: L
authors.lastname: Yin
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002460:Cell Line; D053493:Cholestanetriol 26-Monooxygenase / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; C099252:oxidized low density lipoprotein; D000098682:Steroidogenic Acute Regulatory Protein; D002784:Cholesterol; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase